The category A intracellular bacterial pathogen Francisella tularensis, the category B bacterium Listeria monocytogenes, Mycobacterium tuberculosis, and numerous other important human intracellular pathogens have evolved to benefit from stimulating the host to produce type I interferons (IFN). Our prior studies with L. monocytogenes revealed a mechanism by which IFN can increase host susceptibility to these infections. We found that IFN suppresses the activation of macrophages by causing rapid reductions in myeloid cell expression of the receptor for type II IFN, IFN?. In the R21 phase of this R21/R33 proposal, we will use novel reagents and tools developed in our lab to experimentally test whether host-targeted interventions that prevent down regulation of myeloid cell IFNGR by IFN have therapeutic effects in the context of mucosal and systemic bacterial infections. In Aim 1, we will investigate whether transgenic mice developed in our laboratory that do not down regulate IFNGR in myeloid cells have increased resistance to systemic and mucosal bacterial infection. In Aim 2, we use inhibitors of a host kinase that plays a role in IFNGR down regulation to test for potential pre- and post-exposure therapy. In the R33 phase, we outline our strategy to screen for additional small molecule inhibitors of IFNGR down regulation. We will also characterize the effects of the SM inhibitors and identify their host targets. Aim 3 outlines our screening approach and secondary screens we will use to identify selective small molecule inhibitors of IFNGR down regulation. In Aim 4, we will define the global effects of these inhibitors on constitutive and IFN-regulated macrophage gene expression and use SM inhibitors to identify novel host proteins that contribute to IFNGR down regulation by IFN and thus may be targets for host-directed interventions to treat infectious diseases.